Born in Los Angeles, California, she is the daughter of producers Donald P. Bellisario and Deborah Pratt. Bellisario made her acting debut in her father's 1988 film Last Rites at the age of three. She continued to have roles produced by her father, mainly in television shows such as Quantum Leap, First Monday, and NCIS, and in 1998, she acted in the direct-to-video comedy film Billboard Dad. In 2010, she received praise for her leading performance in the film Consent for which she won the Vision Fest Award for Best Acting by a Female Lead and the FirstGlance Philadelphia Award for Best Actress.

In 2014, she starred in the music video for The Head and the Heart's song "Another Story".[13] Bellisario also starred in Immediately Afterlife, a short film about two cult members who are the only survivors of their group's mass suicide, playing Bennett, alongside her Pretty Little Liars co-stars Shay Mitchell (Marissa), Ian Harding (Paul Fields) and Nolan North (Leader, Voice Over).[14] In 2015, she was cast in a leading role in the American remake of the French-Canadian film Martyrs.[15][16] In 2015, Bellisario and fiancée Patrick J. Adams filmed short film We Are Here in Haida Gwaii, which Bellisario wrote and starred in.[17] In 2017, Bellisario starred in her feature film, Feed, which she also wrote and produced. The film was written based on Bellisario's own experiences with an eating disorder.[18]

On April 7, 2016, it was announced that Bellisario would be directing Season 7, Episode 15 of Pretty Little Liars.[19] This made her one of the first in the cast, alongside Chad Lowe, to direct an episode on the series.

Bellisario started dating Suits star Patrick J. Adams after they met on the set of the play Equivocation in 2009.[20] The couple briefly split, but after Adams' guest appearance as Hardy in Pretty Little Liars, 2010, the two got back together.[21] Since working on Equivocation and Pretty Little Liars, the couple also worked together on the 2012 short film The Come Up, on the USA series Suits in which Adams stars, and the short film We Are Here. Bellisario and Adams married on December 10, 2016 in Santa Barbara, California.[22][23] Bellisario gave birth to her first child with Adams on October 8, 2018, announcing the birth on her Instagram.

Bellisario revealed in early January 2014 that she went through personal problems through high school, resulting in an eating disorder and self-harming problems. "I was the youngest daughter, the perfect little girl," she said. "My school was a very intense college prep school. So it was about wanting to please my father and mother and wanting to be perfect to everybody."[24]

Bellisario delivered the USC School of Dramatic Arts (her alma mater) commencement speech in 2014. "Once you start creating without anybody's permission, you own it. And because you learned it here, you know the power of a story. You'll never feel embarrassed when people ask you, 'What do you do?' You will look them in the eye and say, 'I tell stories.' And people will line up to work with you," Bellisario told the graduating class.[25]